DE1468760A1 - Process for the preparation of 4- and 5-aryl-1-naphthalene acetic acids and their derivatives - Google Patents

Description

DR. ING. F. WTTBSTHOFF DIPI »ING. G. PUIiS DR.BVPBOHMANN • PATENT LAWYERS

TXZ ₁ BFOW 22 Οβ Sl

TBLBSBAHHiDltKSB £ I PBOTiOTPlTIST ΜϋΝΟΗΚΪΤ

1A-27 825 1468760

description in the patent application

Parke, Saris * Company Joseph Caapau Avenue at the Hirer

Detroit 32, Michigan, USA

concerning

"Process for the production of 4- and S-aryl-i-naphthalene" acetic acids, and their derivatives ".

The invention relates to a process for the preparation of 4- and 5-aryl-1-naphthalene acetic acids and salts and esters thereof. More precisely, the invention relates to a process for the preparation of compounds of the general formula

80 9 902 '

where R is a hydrogen atom, a salt-forming cation, a lower alkyl radical or a lower dialkylamino-

2
alkyl radical, R a hydrogen atom or a methyl radical,

3 4 3

one R or R is hydrogen and the other is R

or R is a group of the formula

1st, wherein in this formula Z is a hydrogen atom Fluorine, chlorine or bromine, an o-methyl, m-methyl, is o — methoxy or m-methoxy. The lower dialkylaminoalkyl radical can be in the form of the free base or an acid addition salt.

In the above formula contain the lower alkyl radicals preferably at most 4 carbon atoms · the lower dialkylaminoalkyl radicals represented by the formula

Alkyl
-Alkylene-N ""

^ Alkyl

are represented, preferably contain alkyl groups

pen with a maximum of 4 carbon atoms and the alkyl en-

8 0 9902/0910

group contains a maximum of 4 carbon atoms and separates the groups linked to it by at least 2 carbon atoms.

According to the invention, compounds of the general formula

K ²

CH-COOM

1 * -

3 U
r R ^

made by making a compound of the formula

R ²
CH-Y

Γ ΐ

hydrolyzed, with M in these formulas being a hydrogen substance atom or a salt-forming cation and Y one to one Carbojyl group is a separable group and R, R ^ and R ^ di © have the above meanings. Some examples of ßrup

809902/0910 '

pen that can be saponified to a carboxyl group, are cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, Carbamoyl-, alkyl-substituted carbamoyl-, Trihalomethyl, amidine, alkyl-substituted amidine,

Haloformyl, -αΖ — ΝΗΝΗ «, -C ^ —HHOH -d -— 0-alkyl,

/ WOH / TTH #H ' P -C "-UfH ₂ ," · </ - ^ NHNHg "-C""halogen, and -C * C (halogen) ^ - groups. The type of group which can be saponified on a carboxyl group ΐ is not of critical importance because it is converted into a carboxyl group when the process is carried out * Therefore, the group Y may contain one or more substituents in suitable cases, e.g. alkyl, lower alkoxy groups, halogen atoms, nitro, carboxyl - Or alkoxycarbonyl groups, and if the group Y is basic, it can also be used in the form of an acid addition salt. The expression "group which can be hydrolyzed to a carboxyl group" here denotes both substituted and unsubstituted radicals. Preferred starting materials for the process are compounds in which the group Y is a cyano group, since such compounds are very easily accessible and can be saponified in high yields with the carboxyl compounds.

The hydrolysis can take place under or under Conditions are carried out, 4 are applied

809902/0910

a β aar en or basic, re rs eleven-terminating agent. Alkaline conditions are accepted and are to be applied exclusively to certain groups γ, see B, to the -C * - C (halogen) ^ group. The saponification can in lasse? or in an aqueous solution of a nlcht-reaktionafähigen, misonbaren with water, organic Löaungeoittela be carried out,% "as an aliphatic alcohol, clay Sioxan" tetrahydrofuran "Xthylenglykol, propylene glycol or a lower Alkyläihera το & Äthyltnglykol or τοπ Mäthylenglykol, where m LöeuJägan sin © Acid or base was sugeeet * t to make the medium acidic or otherwise suitable. Bases are, for example, alkali hydroxides, brdalkali hydroxides, alkali carbonates, alicalial alkoxides and trlalkylmonioahydroxides, acids which can be appropriated are acidic acids _P strong ", organic acid" such as p-Tolaolsalfonsaiire and saore loüeaaaetgleichhÄrjss. BsTorsugte% a «i» qn «means aiad AXkftlihyaroJcyd ·, wi · 5atylu« hy4roxyd eier rallwahydroayd. Paa Teratifungeaittal is used in

Dis? «F # 9ifaa§« iTi 4 «rch $ efLihri _t in £ ea aaa eis»

in one

£ Sft «*« a «ittal _t ti« * i »· SSmre or« to · See «« ntliSLlt, # r-

f · Bie Vihreriefliske Bi «« lr «aft feeptratar im 4 | jfl ^ t # ttit «» ι dtsr irt Äer örep? · y oaö des τ «γ-wemiete» vaBis «iien © the eaeren smock. Eat general »

809902/0910

However, the reaction is carried out at a temperature of about 30 to about 200 ° C. or at the temperature of the refluxing boiling of the solvent and for a duration of the reaction of about 1 to about 48 hours. When using one of the preferred basic saponifying agents, the reaction is usually carried out at a temperature of about 60 to about 125 ° G and is largely complete in less than 24 hours, if the saponification is carried out under alkaline conditions, then the reaction product is in the reaction mixture in the form of a salt and can be isolated in this form or after treatment with an acid, preferably with a mineral _{acid 9,} in the form of the free acid Fora the free acid can be isolated directly in this form or by subsequent treatment with a base Ie form.

The use in deaf inasags according to Terfahren Excessive raw materials can be harmful d »n * rtlgea T« rfmhres are made as closer to tea loving. 2. B. körmea 4-aryl-1-aaphtylao "toni" tril «iareii iÄesfiteaag« i »e« i-ArylaepfetÄlin · «it u & d chlorine "s.gs" x "toffic acid i * + -Arjl-1

sit

BATH ORIGINAL - 7

809902/0910

cyanide can be produced in an aqueous medium. A 4- or 5-aryl-i-methylnaphthalene can also be reacted with N-bromosuceinimide to give a 4- or 5-aryl-i-bromomethylnaphthalene and the latter compound can be converted into an A- or 5- / > transfer ryl-1-naphtylacetonitrile.

formula

Furthermore, according to the invention, compounds of

GH-COOH I. i \

■■ * "■

prepared by a reactive metal derivative of a 4- or 5-aryl-i-alkylnaphthalene, which by the formula

R ²

CH-W

BAD ORIGINAL

809942/9930

can be represented, reacts with carbon dioxide in an anhydrous medium and acidifies the reaction product, where in the formulas W is a reactive metal substituent, e.g. B. is a magnesium halide (-Mg halide) or lithium and R, R and R have the meanings given above. The first stage of this process is carried out in an anhydrous, non-hydroxyl-containing solvent, for example a lower alkyl ether, a lower alkyl ether of a glycol, tetrahydrofuran, an aliphatic or aromatic hydrocarbon or a mixture thereof. A preferred reactive metal derivative is a derivative of a magnesium halide, which is usually prepared in situ by reacting a 4- or 5-aryl-i-nalogenalkylnaphthalene with malinesin. If necessary, however, it can be prepared on its own and added as such to the reaction mixture. Approximately the theoretically calculated amount of magnesium is used. An excess is avoided in particular in those cases in which a further halogen atom is present on the phenyl ring. Other reactive metal derivatives can be prepared by generally analogous processes. For example, the lithium derivative can be obtained by reacting a 4- or 5-aryl-i-methoxymethylnaphthalene sit lithium or a lithium alkyl in a mixture of tetrahydrofuran and ether. The reaction with carbon dioxide

BATH ORIGINAL
809902/0910

is carried out, indea a & a »at least the calculated one Amount and presently a considerable excess carbon dioxide of the he & ktlonaaeditia »in which the reactive lethal derirat is present, up. That Solendloxyd can, deactionals also in gaefuralgea or in feetea state sugeeetit be "let warm." not necessary, the reaction becomes old carbon dioxide performed at about 25 ° C or below, then it is usually finished in less than 10 meows Di · 4 «» or 5-aryl-1-naphtheline «* acetic acid is then added naoh Aneänern dee Beaktlonegeaieehee, TorsageWeiae under Terwendang a mineral acid, like Terdünnter Chlor-WÄiteretoffelure or Terdünnter Schwefelsäara, isolated.

In addition, connections of the general Torael

0H-C00E » ^v

T "

CX ^

produced by aan a connection to the general formula

E ²

OH-COOH

H ³ 1 *

or a reactive derivative thereof, a solohen, is reacted, where R ^f is a lower alkyl or lower Bialkylaminoalkylreet 1st and E »E and R besitassn as defined above with lower alkanol, a lower Dialkylaainoalka & ol or a reactive derivative. The lower alkanol, the lower dialkylaminoalkanol and their reactive derivatives serve as residual esterifying gels. Suitable reactive derivatives of the acids are e.g. B. the acid anhydrides, acid halides and the Alkalisalss® of acids. Suitable, reactive derivatives of alcohols are, for. B. various esters such as methyl bromide, methyl iodide, ethyl iodide, propyl iodide, dimethyl sulfate, diethyl sulfate, 2-dimethylaminoethyl chloride, 2-diethylaminoethyl chloride, 2-dipropylaminoethyl chloride and 3-ethylaminopropyl bromide. Other reactive derivatives such as diazomethane can also be used.

- 11 -

BATH
ο η ο η η ■> / rt ο 1

Is the esterifying agent a lower alkanol or a lower LdalLylaminoalkanol, then the drive preferably by heating the free acid or its anhydride or halides with an excess of the lower alkanol or lower dialkylaminoalkanol carried out. If the free acid or the anhydride is one of the reactants, then an acidic catalyst is used, such as hydrochloric acid, sulfuric acid or Benaolsulfonic Acid. Other solvents, such as tetrahydrofuran, Benzene, dioxane or diethylene glycol dimethyl ether can optionally be present. The reaction becomes ordinary at a temperature of about 25 ° C or more, preferably at 60 to 150 ° C, but not above the Tem- ' temperature of the back-flowing boiling carried out and is usually with the free acid in 5 to 100 hours or with the anhydride or halide in 1 to 5 hours completed.

If the esterifying agent is an ester of a lower alkanol or an ester of a lower dialkylaminoalkanol, As indicated above, the process is preferably carried out by adding the acid or its Salt with the appropriate halide, sulfate or a another ether derivative in a solvent in the presence a base warms. Suitable solvents and see B.

- 12 -

5 09902/0910

lower alkenols, tetrahydrofuran, dioxane, dimethylformamide, Diethylene glycol dimethyl ether and mixtures thereof. Suitable bases are ε. B. inorganic alkalis or tertiary organic amines. At least the equivalent amount and Preferably an excess of the esterifying agent is used. The reaction is usually carried out at a temperature from about 25 to about 150 ° C, preferably from about 50 ° C 100 ° C. And under these conditions is within Largely finished in 24 hours.

If the esterifying agent is diazomethane then the process is preferably carried out in a non-reactive one Solvents such as ither, tetrahydrofuran, diethylene glycol dimethyl ether or dioacan. The reaction happens very quickly and is preferably done by treatment of the free acid with the equivalent amount or a small excess of diazomethane at 0 to 25 ° C. Under these conditions, the esterification is completed in less than 5 minutes.

During the manufacture of the articles of the invention. Dialkyl ainoalkyl ester can make that product by setting the pH value it either as a free base or as an acid addition to be isolated.

The free acids and free acids according to the invention

BATH ORIGINAL. - 13 -

809902/09 TO-

BM · η part4 «a 8» 3. * e «it vlftltn organic

• cfcea Baaen or Slar · », aeeigaete lasen are s, 3« ie » triaahytroxyö, K * Uiaskyi * $ * y <l, Oaleiaabyäiroaryä, fairina *

siftk uttd diethyl «ia« »« «igaet» S * ar # n elaA ». B.

_t Br «wwr» * 9ers »i # ff« säure, Sohwef # l «au»

rt, Fho * pho3N | ! ··! £ ·, Xitronaa-, Wein- and lyftninngggwia »« yorg «gt» »» rboneanre 3al »a are the phantwt» tigah «at« 9igeB Sale «eino» Alk * li »rfcfcll«, «1-n ·· lru »lkmli» «t * lle _t το * Aaaeaiak or eia * a aubstitai« rt · * AeeoBlak, BftTomugt · erf induagsgeeää «acid addition» «*! ·« «Lad di · S * iae ttit mineralic acid« s, Di · Carbonate * ¹ »a Sei« · end ii «Sä« r «* dditii> jyi» * lie »it phar» aseu ~ ti »oh amlfi *« if * n laUon «. and Aaioaea unt "r" oh "i" Jen see in ilirea I "ö" Ii <9iik "ltE" if "neöäaften τοη the free acids" ad free B """ß, * iad but otherwise for the 2wack" der equivalent "

a * eh 4er invention "isiä nea *" eaeai «ea # TejreljUaafeÄ» üe «1» pharmakoloiiephe effective » itoffe mad al «eheaiee & a Swieohenprodmk-ke valued ice, Si · »i & A entiü» de »s» wi4rig · Wiyicetoff · aad feöjSÄea «ur Lialeraa «fi» i1ime> f | j | »lii» y Sastäad «aaä eur Teffeettgasg or leM ^ fttiie ** · A «ftr *** a« by SatsiSaisag · * vwm * M »t w« s ^ - his * fM will be »veyaaeeweiee fer # ral. verimreiatoi, köanea

- 14 -BADOBI (SiNAL

8 09 9 0 ί 7 0910

1468780

-H-

However, you are administered parenterally. Al "" ntiüsidöstgs "" adverse active ingredients are 4 "Hienyl ~ 1-iiapfetalin" * sig8äu: r "and 5-phenyl-1-naphtalia * ssig; all tvvomnkgt" B & es "a rl el higher Sr« d γοη desünäangewldrlge? “Aft than this normally becomes healthy in Kleht * 3t« roi & «ii. Other preferred anti-inflammatory agents are the o- and m-halogens "nTerfei" dungeii, some of the ¹ ®r-

Verbiadtingon besii & en && g2i. "Vein*, Sigeneohafttii. E.g. B * are ^^ esy

and ^ -Phenyl-1-naphthalene acid "

eten of the '. effect of Bradjkinin and are as aatiallerglsoh "active ingredients waToll" The invented tarnish can "n in the Torah of the free acids, their Esier or? their S & lä * and combined with a solid or liquid carrier or diluent or used in Tersehledenen Meng «® in the form of pharmaceutical preparations such as Teiletten, sein, powders and aqueous and nodular-aqueous and WawagQn «

BIe Srflndong is based on examples Bäh explains «

example 1

won 12 β Kftli «£ fcyäröxyd is 50 si What» 8 * r will be added to a solution νοη 5 _t 7 g 4 * Hi @ ayl-1-napiat ^ ylai5eto «» nitrile in 80 al Xthanol Mneage and the G * Ri »ch 16

809 9 0 2/0910

the heated to refluxing boiling, concentrated under reduced pressure to a small volume, diluted with water and washed 2 times with ether. The aqueous phase was acidified with dilute hydrochloric acid and the insoluble 4-phenyl-1-naphthalene acetic acid was collected on a filter. After crystallization from Bensol-Heacan, the compound melted at 120.5 - 121.5 ° 0.

1 g of sodium carbonate was added in portions to a solution of 5 »0 g of 4-phenyl-1-naphthalene acetic acid in 50 ml Methanol given. The mixture became flowing back for 30 minutes Heated to the boil and then evaporated to dryness under reduced pressure, whereby the sodium salt of 4-phenyl-i-naphthalene acetic acid in the form of a white Powder received.

The solution of 2.4 g of choline chloride in 10 ml of methanol was added to a solution of 5 »0 g of the sodium salt of 4-phenyl-1-naphthalene acetic acid in 50 ml of methanol. After 1 hour the insoluble sodium chloride was filtered off and the filtrate was evaporated to dryness under reduced pressure to give the choline salt of 4-phenyl-1-naphthalene acetic acid as a white solid.

- 16 BAD ORK

809902/0910

A Wmmg γαη 0.33 g ammonia la 10 al methanol was added to a solution of 5.0 g 4-Fh $ nyl-i-ne, phts, line acid in 50 ml methanol and the gtealeoh ear trookene was poured in the ammonium hydroxide of 4-phenyl-1-naphthalene acid was obtained as a white solid. If the aasomiak was replaced by 1 * 4 g of Dläthjlaeiü and, by the way, drove into an analogous orphan ₉ then you got that

ron 4-2 & enyl- »1« -naphtallneastgeäur ·.

The starting material could be manufactured as follows

Is it made from 100 g of 1-Phenylnaphtmlia ₉ 2? Paraformaldehyde, 100 μl of acetic acid, 112 tablespoons of concentrated hydrochloric acid and 54 ml of phosphoric acid were heated to 88-91 ° C with stirring for 12 stalls, with a further 30 ml of concentrated hydrogen chloride being added in portions at intervals during the heating process Hours b & i Rouimtea & per & tar stand and then poured into water · The water was decanted off

and eating yellow in chloroform "the chloroforosloan" is water "ait saturated xatriuabi carbonate""ag and again aehraals old water!" wash * getroeksat and inter Terainderea Druok potted "wolrei aaa eiA" m lü "lc" was tone 4 "¥ hot ^ l "t ~ ohloraethylaapht $ 3, is, ml% 4" a Xp * 141 * 1SoVo, 25 η *** mU * n _f & * v mak am aierem of the distillate min hexane is called $ 4® Cl

809902 / OSfö-

A solution of 25.2 g of this product in 150 ml of acetone and 100 ml of ethanol was treated with a solution of 4.9 g of sodium aoyanide in 30 ml of water and heated to refluxing for 5 hours. The solvent was removed under reduced pressure and ά The residue was stirred with water and chlorinated oil. The chlorofonal solution was separated off, washed with water, dried and evaporated under reduced pressure. after crystallization, ben «ol-Heian obtained» en 4-phenyl-1 * aßphtylaoetonitril,

with at fp. 102 - 103 ° 0.

Example 2

Seaweed from 50 g of space hydroxide in 75 ml of water was dissolved in a solution of 27 _f 2 g of 4- (m- "4-ethylphenyl) -1" naphthyl acetone Heated to the boil and then concentrated to a small volume under reduced pressure, the remaining mixture was diluted with water and washed twice with ether. The aqueous phase was separated off and acidified with dilute chloroformic acid - "(m-Methylphenyl) -el-naphtalineaaigiäare siaa ah and was collected" After several crystallizations from Bensol-Haxan and from aqueous ethanol lohmols die? erbind * af at 124 - 125.5 ° C.

If the 4- (m-xethylphenyl) -1-naphtylao-tonitrile was added by 27.2 g of 4 ~ (o ~ M'thylph * nyl) ~ 1-naph1; yl ~

j * tO ^s - 18 -

BAD ORIGJNAl.

acetonitrile and proceeded otherwise as above beeohriebea » then you got 4- (o-methylphenyl) -1-naphtalix} .acetic acid; acid *

The starting materials were prepared from 1- (m-M @ thy! Phenyl-naphthalene. and obtained from 1- (o-methylphenyl) ~ naphthalene "

Example 3

A solution of 20 g of xalium hydroxide in 50 ml of water became a solution of 22.7 g of 4- (m-gfalorphenyl) -1-naphtylacetonitrile added to 150 ml of ethanol and 100 ml of dioxane * The resulting mixture contained two layers. It was heated with stirring for 18 hours heated and then concentrated to a small volume under reduced pressure. The remaining mixture became Distributed between water and ether and the aqueous phase separated "acidified with dilute hydrochloric acid and extracted 2 times with ether. The combined ether extracts were washed with water, dried and evaporated under reduced pressure, leaving 4- (in-chlorophenyl) -1-naphthalene acetic acid remained as a residue. After recrystallization from Gyolohexane and from aqueous ethanol schmolai the connection at 143 - U5 ° 0

The starting material was based on the general Procedure of Example 1 from 1- (m-chlorophenyl) naphtalias

- 19 -

8099Ö27Ö ^! 9i0
BATH

U68760 • 19 -

obtained Bas 1- (m-chlorophenyl) naphthalene was obtained, By using the monomagnesium derivative of 3-chlorobromobenzol with 1-0x0-1,2,3,4-tetrahydronaphthalene in ether on reaction brought the reaction mixture saponified with dilute hydrochloric acid, and the product with 20% sulfuric acid heated and the obtained 4- (m «-Cfalorphenyl) ~ 1, 2-dihydronaphthalene by heating with sulfur for 30 minutes dehydrated to 215 ° C.

Example 4

A solution of 10 g of Ealiumnydroacyd in 23 ml of water was added to a solution of 10 g of 4- (o-chlorophenyl) «1-naphtylacetonitrile in 100 ml of ethanol and the mixture was heated to refluxing for 18 hours, with reduced sruok to a small volume concentrated, diluted with water and washed twice with ether. The aqueous phase was separated off, acidified with dilute hydrochloric acid, and the insoluble reaction product, 4- (o-chlorophenyl) -1-aaphthalene giacid, collected. After repeated recrystallization from Beneol-Heacan sohmols, the compound partially _{solidified again at 171 ° O 9} and eehmols again at 184.5 * 186 ° C.

The Auegangeamaterial could be obtained ₉ as follows

tO f magnesium were mixed with 80 f o-chlorobroabenaol

BAD OF & INaC - 20 -

and an iodine crystal in 125 ml of ether to react, 64 g of 1-0XO-4-methy1-1,2,3 »4-tetrahydrqnaphthalene in 100 ml of ether were added, the mixture was heated to refluxing for 1 hour and then heated. The product obtained from the ether solution was converted into 4- (o-chlorophenyl) -1-methyl-1,2-dihydronaphthalene with 250 ml of 20% sulfuric acid by heating the tower at 80 ° C. for 30 minutes. This product was converted into 4- (o-chlorophenyl) -1-methylnaphthalene by heating with an equimolar amount of sulfur at 215-220 ° C. for 30 minutes, followed by vacuum distillation, aluminum oxide chromatography and crystallization from hexane, whereupon the product melted at 72-73 ° C. A solution of 10 g of the product in 100 ml of carbon tetrachloride was treated with 7.05 g of freshly crystallized N-bromosuccinimide and 200 mg of dibenzoyl peroxide, and the mixture was refluxed for 18 hours under floodlighting heated to the boil. It was then filtered, extracted twice with a 5% sodium hydroxide solution and several times with water, dried and evaporated under reduced pressure. After recrystallization from benzene-hexane to give 4- (o-chlorophenyl) -1 'broinmethylnaphtaiin, to the IP 122.5 - I23 _t 5 ° C. A "solution of 13 g diesee product in 50 ml acetone and 50 ml Ethanol came with a solution

- 21 - ■ ■

809 902/09 10

τοπ treated 2.06 g of sodium cyanide in 10 ml of water. Bas Mixture was warmed to reflux for 18 hours, under yerdmintertem pressure to a small volume • evaporated, diluted with water and extracted with zither. The ethereal bait was dried and evaporated, whereby since 4-Co-chlorophenyl) -1-naphtylacetonitrile received, the was suitable for use without further purification

Example f:

A solution of 50 g of potassium hydroxide in 75 ml of water was added to a solution of 40.9 g of 4- (m-broiaphenyl} -1-naphtylacetonitrile in 500 ml of ethanol and 100 ml of Bioxaa iugegefeeii »Data 0eaieoli was sent back for 18 hours Boiling warmed up, amtty Tersindestem Drublc to a little ToXiaM »eiefMöft,« 4% Was »tr Ttrdünnt and 2r-a« l with Xtfeer gewasohea. The vaserig "Soäiolit" erde "!" Separated and ait TerdUnmter Cfcltrw * «e« r «toffsiare aageafiuirt, pie ualöelioh«

«At tetasli a« ee mhftmh ** ®aÄrißtallielar »n an»

ö55 ° 0,

Jtt «§s * StB **« r £ «& MUNI« ft «#li « Uft * llg * aeinem

»Tietiel

mm mmm'w * m §imM ^ k & m * $ & ta η

22 -

■ - 22 -

Water was added to a solution of 22.4 g of 4- (ai-fluorophenyl) «-1-naphtylacetonitrile added in 2QO tnl ethanol. The mixture was heated to a flowing boil for 18 hours » concentrated to a small volume under reduced pressure, diluted with water and washed twice with Itherg ©. The aqueous phase was separated and acidified with dilute hydrochloric acid, precipitating a precipitate obtained from 4 ~ (m-I ^ uorphenyl5 ~ 1-naphthalene8acetic acid » after repeated recrystallization from benzene-hexane 145.5 - 146.5 ° C melted.

The starting material was based on the general one Procedure from example 4 to age 3-bromofluorobenzene

Example 7

A solution of 30 g of Γείΐumhjdroxyd in 75 ml of water was added to a solution το »18 g of 4- (p- ¥ luorpiieiiyl) -1« aÄpli «» · tylaoetoaitrile in 2QO ml of ethanol. Thereupon throws "i & 9 aaarei" ii * ßd · quantity of Diöxan _for something like TS stl _r sagegelieia " mm a homogeneous" solution hersestellea WRä diaoe on this 13 stand suai refluxing boiling "nrmtf under d" rte "click on a little" Yoluaeju cut in , bit "Er T" 2-diiaat and 2 * aa | ait Ith «· gtw & iohefi. The wäaari ^ a Aiigets «imt asä old

BATH OftenKSiNAfe. 809902/0910

- 23 - ■■

4- (p-i'luorophenyl) -1-haphthalene acetic acid was collected and melted from 'enzol-Ilexari after 2-fold detailedization at 162-163.5 ° C

The starting material was prepared according to the general procedure of Example 4 from 4-'brorofluoro' benzene.

Eeisoiel 8 ■ · .. ■■■ ". ■■

One. Solution of 30 g in 75 ml Kaliuruhydroxyd '' as-Ser was added to a solution of 24 g 3 _f 4- (ru-iiIetlio ^ .ypheriyl) -1-naphtylacetonitril added in 200 uil ethanol and 50 ml Moxan. The solution was heated to constant boiling for 4 hours, concentrated under reduced pressure to a small volume, diluted with water and washed twice with ether. The aqueous phase was separated and acidified with dilute hydrochloric acid. The insoluble, oily product was extracted with ether and the ether extract was washed with water, dried and evaporated under reduced pressure, the 4- (m-Iiethoxyphenyl) -

obtained which, after repeated recrystallization, also melted benzene-hexane at 11G, 5 ° -118.5 ° C.

Replacing 4- (m-'vjethoxyphenyl) -1-naphtylacetonitrile in the above process with 24.3 g of 4- (o-methoxyphenyl) -1-naphtylacetonitrile gave 4- (o-metlioxyphenyl) -1-naphthalene acetic acid, 1

- 24 -

BAD OpiftftAto rf

809902/09 10

The starting materials were prepared from m-bromanisole and auss o-bromanisole according to the general procedure of Example 4 manufactured,

Example 9

A solution of 11 g of potassium hydroxide in 35 »1 Water was added to a solution of 11.1 g of 5- (m-fluorophenyl) -1-naphtylacetonitrile in 110 ml of ethanol «added. The mixture was refluxed for 12 hours and then concentrated to a small volume under reduced pressure. The remaining mixture was with Diluted water and washed 2 times with ether. The aqueous layer was separated, washed with dilute hydrogen chloride acidified off acid and the excreted insoluble Product extracted with ether. The ether extract was washed with water, dried and evaporated, whereby one a residue of 5- (m-fluorophenyl) -1-naphthalene acetic acid received. After repeated recrystallization from cyclohexane, this compound melted at 127 »5 - 129.5 ° 0 *

The starting material was obtained from 3-bromofluorobenzene and 1-0xo-5-methyl-1,2,3,4-tetrahydronaphthalene following the general procedure of Example 4.

Example 10

A solution of 7.6 g of potassium hydroxide in 20 ml

* JAl-H 'i'K ■■ -. · ■.

B * D ORIGINAL " ₂ 5 -

809902/0910

Water vast · eiatr & 8 »« ag ^of 7.5 f 5- (o-Cklerpfetnyl) -1 * n «phtflM« toftltTll ia 75 al ithaael »aftf · * ·» »Da» ■ isea «art · 12 State ·« ta «rKtfeflitieafttit 8iet« a «xviyBt hitraaf« at «r

lwitm · ΐΒ (Μ »β%. B« r lä »k» t «» A will · sit W «eer rtrdiinmt «At 2-s * l» It lth «i gtwMeht». The ^ serig · flu »·

«Ad ait TerdtlnBter Ghlorw * s *» ra4oXf * äar · C «* l« «rk · Β ··«% fBe «ai« i · «·· waöeUthe 9 *« * «kt become ait timw ί «α ·· Β *** itlwr« s4 IthylMtint «xtfaliiert« aft Ü · orfnUok · (0 «« ai ait

«Aft» iai «iMijpf t« where aaa Ji • «aigslbur ·« la Küokatmnd «rhitlt. lach Repeated * Qalcri- • talli «i« 7 · » mem Aattoaltril eoh» ol * ftieec ferbiisftaitg fe «i 203 - 205 ^f 0 ·

Ham Auag "xtgSMftterial t rhi" It men "as © -Chlorbro" - btseol "ad 1-0zo-5-a" thyl-1 _f 2,3,4-tttreÄyäronaph-kftlin after dt "allc" a "iiien Y erf Ears gate Btiepiel 4 «

l "ispi" l It

lia · ItÖeaa «ταα 12.4 g üliamhyÄroxy« im 40 al fuiir «« yft · ei »« r Lösiuag το »12.4 f 5« fhtayl-1-ÄÄphtyl- «•• ^ • fiitril ia 125« 1 It * e * «l Β · § · β» ί) «», tat «« aiaeli 12 State * »« at rO * kmtl »« 4 * Si «den erwtrat, aitvaef« at «r ▼ • rmlBft * rt ·« 2> »« «k aaf« ia kltim ·· Το1 «· η« ias «eftgt _t alt WMa # r Ttrfiüiimt« aft 2 «aal alt l \ h * r fr» a * ch »ai. The wliari-

- 26 -

BATH

. _t / l- ■ ■■■, ■■ * r;

809 902/0910

ge layer was thinned CfcleF "**" "re% of * säsr * acidified and you «uegesehied ·» «JÜöeliche sit lther «radiates · D * r ltb ** M% n * t would get old jot gsv & seneii · dried and ice »d3» pf fc »where ια 5-? H «ayI ~ 1-» ap $ italia * i »lfiäaF *« ι «iltekstea * received laughable recrystallization as · Β · ηκο1 «-Ξ · χβ & βohmole this «connection at 160 - 182 ° C.

Auegang «attrial kofiät ·» wl · follows »receive» tea will be

10.5 S ttakrietallized H-BroMiueoiBisid and 100 Bg diberiaoyl peroxide were added to a solution too. 12.6 g of 5-? 5ienyl-1-a "thylnftphtaiin in 125 el Tetraohiorkohlenatoff xu and heated 2 Standen under Beatrahlung with Fl" tlieht suzt raokflieBenden boiling · Then the mixture is filtered, washed the f lltrat old a 5 ^ strength and Hatriuabydroxydlöeung a «hxaals lait Waesör, dried and evaporated» with the residue 5 »phenyl-i-fcroaatethylnaphthalene obtained, line VSmwag tozl 15.9 g of this product in 75 alcohol and 15 bl acetone with a solution of 2.7 g Hatrlumcyanid treated in 15 ml of water. The Löesan was heated to the boil for 5 hours, followed by tenindertes Druok on ice-cream bran and diluted with ether. You Xtherlösung was with barrels washed, dried and eing "£ aapft _r where mas 5-Pii * nyl-1-r: £ pfetjtlacefonitril received, the aur without further purification

Use was suitable

809902/09 10 BAD OPHQfNAt - 27 -

Example 12

A mixture of 12 g of O ( -Methyl-4-phenyl-i-naphthalene acetic acid ethyl ester, 12.5 g of potassium hydroxide and 125 ml of ethanol. Was heated to refluxing for 20 hours and left to stand for 2 days at room temperature. The ethanol was distilled off and the residue with 100 ml of water were stirred and washed with ether. The aqueous solution was acidified with dilute hydrochloric acid and the insoluble 0-methyl-i-phenyl-1-naphthalene acetic acid was filtered off. After crystallization from aqueous acetic acid, this compound melted at 125 ° -126.5 ° 0.

The starting material could be obtained as follows:

A solution of 13 g of 4-phenyl-1-naphthalene acetic acid, 150 ml of methanol and 3 ml of concentrated sulfuric acid were heated to refluxing for 17 hours Distillation of the solvent concentrated to a small volume and diluted with 250 ml of water. The aqueous mixture was extracted with several parts of ether and the ether extract with water, dilute sodium bicarbonate solution and water, then dried and evaporated, whereby 4-Pheny1-1-naphthalene acetic acid methyl ester remained as a residue. This product (about 13 g) was dissolved in 16 ml of dimethyl sulfoxide and the solution was added dropwise with stirring and cooling a mixture of 2.6 g of a 53ρ4 ^ igen suspension of sodium hydride in mineral

. »; ■ .- ■ -... H ■■ BADORJGJNAL on

809902/0910

oil and 9 ml of dimethyl sulfoxide given. The reaction was carried out under anhydrous conditions in a nitrogen atmosphere, the temperature being kept at 15-35 ^° C. Bas red Reaktions'jrigemiseh was stirred for 1 able to sum or cessation of hydrogen evolution at room temperature · With continued stirring and cooling to below 55 ⁰ C. 8.3 g Methyljοdid was slowly sugegeben and the resulting thick slurry stirred for 18 · hours at room temperature To this was Excess sodium hydride is decomposed by carefully adding a solution of clay to 1.5 ml of acetic acid in 10 ml of borneol. 100 ml of water were then slowly added and the mixture was extracted several times with ether.

Example 13

A mixture of 10 g of 4-Pheny1-1-naphtalinesβigsäureäthylester, 10 g of potassium hydroxide, 25 ml of water and 100 ml of ethanol was refluxed for 4 hours The residue was diluted with water and 2-eel washed with ether. The aqueous solution was acidified with dilute hydrochloric acid and the

- 29 -

80 9902/0910

Auegeaohiedene 4-Phenyl-1 ~ naphthaleneaiga acid filtered off "laugh Uakrietallieieren from Sensol" * Rexan βchoc1 * This is at 120.5 - 121.9 ° E.

DaBielbe product was obtained by looking into. The above «method the ethyl te t he dee 4-phenyl-i-aaphtalirL-acetiMideäarehydrobromlda used

De »Aaagangaeaterial could get as follows» will be

Bin · üÖBung iron to g 4-phenyl-i-naphtylacetonitrile in 100 ml lth «r _r containing 1.9 β ethanol» was cooled to -15 ° Q and gaaföraiger broawaeaeretoff poured in, feia daa approved diinoether hydrobrobiide (Xthyl · «•• tear de * 4-Pßenyl-i-naphtalinaoetimidsäurehydrobroaida) aaaflel. The raw product was collected on a filter, 5 i of the baby hydrocarbons were dissolved in 25 ml of cold water and allowed to stand for a few minutes. las auegeeeaieAeae was oil m% t Ben "oil extracted and * it geiättigter latriuabioarbonatlöaun" on "> eel old gewaaohen Waaaer, dried wid OXITER appointment Disability" dey Beaiolextrakt "Sraok evaporated to give aam 4-phenyl-1 * napatalineeelg" lureätayleattr erSUelt, the level further teinlgaat only TerweadaBg geei £ »et was *

BAD ORIGJMAU

$ §S902 / QSI0

Example 14

A mixture of 10 g of 4-phenyl-i-naphthalene acetamide, β g sodium hydroxide, 30 ml water and 120 ml Ethanol was boiled 5 levels to the riiokfließeadon he " warms to a small volume under reduced pressure concentrated »diluted with water and washed with ether · The aqueous solution was separated« with dilute Hydrochloric acid acidified and the excreted * insoluble 4-phenyl-1-naphthaleneesig® acid collected on a filter. After recrystallization from benzene-hexane echmol * the enmity at 120.5 - 121.5 ° 0.

Bass same product obtained m n _f when 1 »naphtalliieesigsäurehydrasid used in the above process d§s 4" Ekenyl "e.

The raw materials could be obtained as follows will be

A ksuag of 5 g of the ethyl acetate of 4-phenyl-1 »naphtaXiiiacetimid8äurehydrobromää in 50 ml of acetone was heated to the boil for 30 minutes and evaporated under reduced pressure »whereby one aas 4-Phtnyl-1-naphthalene acetamide received «

A mixture of 10 g of 4-phenyl-1-naphthalene. «SsBige acid ~ ätiiyl *« ter »8.1 § 85 $ ± & n hydr» iinhydrate and 40 ml

BAD ORIQiKfAL - 31 ··

809902 / 0Ö10

Ethanol was heated to refluxing for 4 hours and then cooled down. The insoluble product was filtered off. This was the 4-phenyl-1-nphatalinese acetic acid hydrazide

Example 15

A! Solution of 10 g of 4 ~ phenyl-naphtalinaeetamid 1, 100 ml of diethylene glycol dimethyl ether and 50 ml of concentrated hydrochloric acid was heated for 10 hours at 100 ⁰ C and diluted with water. The insoluble product was collected on a filter and extracted with sodium bicarbonate solution. "The sodium bicarbonate solution was filtered and the filtrate acidified with dilute hydrochloric acid" to give a precipitate of 4-phenyl-1-naphthalene acetic acid, which melted after recrystallization from benaol-hexane Connect at 120.5 - 121.5 ⁰ C.

The same product was obtained when using the hydrasside or the methyl or ethyl ester in the above process Clay used 4-phenyl-i-naphthalene acetic acid;

Example 16

A mixture of 10 g of ^ -phenyl-i-naphthalene acetamidine, 10 g of potassium hydroxide, 50 ml of water and 125 ml Ethanol was heated to refluxing for 4 hours, concentrated to a small volume under reduced bridge, diluted with water and washed 2 times with ether

α \ 9 - 32 -

8 09902/0910

The aqueous solution was separated off and acidified with dilute sulfuric acid. The "insoluble" 4-phenyl-i-naphthalene acetic acid which has separated out is collected on a filter. After recrystallization from hexane, the compound melted Benno1-hei 120.5 to 121.5 ° C _t

The source material could be obtained as follows will"

A solution of 28.9 g of 4-phenyl-i-naphtalinaoetimidsäureäthylesters In 100 ml of ethanol 75 tigern as "5t35 g Ammoniumehlorid contained, 4 hours at 70 ⁰ O was heated and diluted sur precipitation of the ammonium chloride with acetone. The aramonia chloride is filtered off, the filtrate is diluted with a further amount of acetone and cooled to 0 ° C. for several hours. The precipitated 4-phenyl-1-naphthaleneoetamidine hydrochloride was collected on a filter and the free base was obtained from this compound by neutralization *

Example 17

A solution of 12.6 g of 4-phenyl-methyl-methyl-1 naphthalene in 50 ml ether was added in portions under rest * 1.2 g of magnesium in 20 ml of ether are given, whereby the The addition was carried out at such a rate that the reaction mixture Constantly refluxing, "Das Se" boiled, which is 4-phenyl-1-naphthylmethylmagnesium chloride

- 33 -

809902/0910

after the addition was complete, the mixture was stirred for 1 hour at room temperature and an excess of aerated, solid carbon dioxide was then stated. The mixture was left to stand for a few minutes and then saponified by adding dilute hydrochloric acid with stirring. The ether layer is separated off, washed with water, dry-kneaded and evaporated under reduced pressure in, "an 4-phenyl" leaving 1-naphthalene acetic acid as residue. After crystallization from Bemol hexane aohmol »this bond at 120.5 - 12l _r 5 ° C *

If you use the above procedure to use 4-phenyl * 1-ohloraethylnaphthalene by 13.3 β 4- (n-methylpiienyl) -1-chloromethylnaphthalene, then / one obtained the "4 - (" - Kethylphenyl) -. 1-naphthalene "8ige acid, which after repeated Uiütrietallieieren from Beneol-Hexane and from aqueous · » Xthasxol at 124 - 125.5 ° C schools,

If the 4-phenyl-1-chloroethylnaphthalene was substituted in the above process with 14.3 g of 4- (m-chlorophynyl) -1-ehlormethylnaphthalene, the 4 - ("- oleorphemyl} * 1" n "pij% «Liae * Bigeäare _# die naoh de» recrystallize aas oyolohexane and an aqueous · «ethanol at 143 *

1 g of Ia | ri «warbonat» is added to the serving white

-34-

809902/0910

a solution of 5 »O g of 4-Pheny1-1-naphthalene acetic acid in 50 ml of methanol su «The mixture became refluxing for 30 minutes Heated to the boil and then evaporated to dryness under reduced pressure of 4 ~ phenyl-1-naphthalene acetic acid in the form of a white Powder received.

The starting material could be obtained as follows

By heating 1-phenylnaphtalin _f paraformaldehyde and concentrated hydrochloric acid in an α "Miach of acetic acid and phosphoric acid to give 4-phenyl-i-chlormethylnaphtalint with the ϊρ · 62-64 ° 0 .. Duron heating 1" (m * liethylphenyl ) naphthalene _f parafonaaldehyde and concentrated hydrochloric acid in a mixture of acetic acid and phosphoric acid gave 4 * (m-methylphenyl) -1-chloromethylnaphthalene. " with the Kp 160 - 185 ° / öt5 - 0.8 Torr. 4- (m * chlorophenyl} -1-ohlormethylnaphtalin "with the Kp 130 -. 170 ° C / 0 _f 15 - 0 _t 2orr 6 was obtained by preparing the mono-magnesium derivative of 3-Ohlorbromhenaol ^ this it in jtther» 1- oxo-1 '2 ^ 3f4-tetrahydronaphthalene aur reaction brought "the fiaaktionaprodukt old dilute Chlorwaaserstoffeäurelöeung hydrolysiert8, follow with a 20 3chw" fel * äurelösung "for BthydratisieruRg heated, the entatandene 4- (m ^ 3Jilorph" nyl} _-1> i '-dihydronaphtaXitt in 1 ^ Ca-Cfelorphenyl) · aaphtalin by heating with sulfur "and fci" r-

809902/0910 -35-

on the product with paraformaldehyde and concentrated Hydrochloric acid in a mixture of acetic acid and phosphoric acid.

Example 18

A clay solution of 1.8 g of 4-phenyl-i-naphthalene acetic acid in 100 ml of methanol, the 10 ml of concentrated hydrogen chloride acid was refluxing for 18 hours Boiling warmed up. The solvent was removed by distillation under reduced pressure and the Kiickstand dissolved in ether. The ether solution was saturated with Sodium bicarbonate solution and several times with water washed, dried and evaporated under reduced pressure, the 4-phenyl-1-naphthalene acetic acid

methyl ester received-. This was used for cleaning in vacuo distilled and collected at a bath temperature of 165-175 ° C below 0.1 Torr.

The 4-phenyl-i-naphthalene acetic acid was replaced in the above process by 4- (m-methylphenyl) -1-naphthalene acetic acid, then 4- (m-methylphenyl) -1-naphthalines were obtained acetic acid ethyl ether.

Example 19

A suspension of 1.8 g of 4-phenyl-1-naphthalene esBig acid, 75 ml of methanol, 1.0 g of potassium carbonate and 5 ml

- 36 -

809902/0910

U68760 - 36 -

Methyl iodide was heated to refluxing for 2 hours with stirring. The mixture was then cooled to room temperature and stirred for 1 hour with a further 7 ml of methyl iodide. The mixture was then poured into water and extracted with ether. The ether solution was washed with NatriuabicarbonatlöBung and repeatedly wiped with water "over sodium sulfate and evaporated under reduced pressure to give the ^ phenyl-I naphtalinessigsäuremethyleBter · This was distilled at a bath temperature 165-175 ° C 0 _t 1 Torr" .

The same product was obtained if an Xther solution of diazomethane was added to a solution of 4 * phtnyl-1-naphthalene acetic acid added in ether at 15 ° 0,

Example 20

10 g of 4-phenyl-1-naphthalene sweet acid chloride was obtained therefrom Stir slowly 80 ml of methanol added * The The mixture was carefully warmed to the boil and allowed to reflux for 1 stand. Bann steamed under reduced pressure, the residue being methyl 4-phenyl-1-naphthalene acetate remained behind. This distilled under at a bath temperature of 165-175 ° 0 OfI Torr

- 37 -

809902/0910

If you replaced the methanol in the above procedure by 60 si n-propanol, then mau dta 4-phenyl-1-naphthalene acetic acid-n-propyleet © r «

The Aueganga material was obtained as follows: 25 g of 4-phenyl-1-naphthalene acetic acid were added with 100% of thionyl chloride while stirring. When the addition was complete, the mixture was heated to the boil and was left boiling for 5 hours. The excess phionyl chloride was then distilled off under reduced pressure, and the 4-phenyl-i-naphthalene acid chloride was obtained without further purification mat use was suitable

Example 2t

A solution of 2.0 g of 4-phenyl-i-naphthalic acetic acid in 100 μl of ethanol, containing 10 ml of concentrated hydrogen chloride, was heated for 18 hours to a low boiling point Reduced pressure was distilled off and the residue was dissolved in ither. The ether solution was heated in a saturated organic sodium carbonate solution and washed several times with water, dried and evaporated under remainder of the pressure, whereby San received the 4-phenyl-i-naphthalene more hotter distilled acid a bath temperature τοη Π5 - 18 $ ° 0

- 58

809902/0910

Example 22

A mixture of 12 g of 4-phenyl-1-naphthalene acetic anhydride, 75 ml of ethanol and 0.1 g of concentrated sulfuric acid were left to boil for 5 hours heated and then evaporated under reduced pressure. The oil was extracted with ether. The ether extract washed with dilute sodium bicarbonate solution and with water, dried and under reduced pressure evaporated, whereby the 4 ~ phenyl ~> 1-naphtalineasigsäureäthylester received · This distilled.at a bath temperature from 175 - 185 ° ö below 0.1 Torr.

The starting material could be obtained »as follows *

6 g of sodium carbonate were added in portions to a solution of 30 g of 4-phenyl- 1-naphthalene-acetic acid in 300 μl of methanol . After the end of the period, the food was heated to refluxing for 30 minutes and then under reduced pressure evaporated to give the solid atrium as 4-phenyl-vnaphthalene sig8 acid. 28 g of 4-phenyl-1-naphthalene-eesigaic acid chloride are mixed in seaish from 28.4 g of catrium salses of 4- phenyl-1-naphthalene acetic acid and 300 ml of dimethylformamide, Jia * aeaisch was further 2 were stirred and evaporated to this udder reduced pressure stubborn dryness · the Rüoketanä will extracted with Btnzol and Sensollö "

809902/0910 - - 39 -

U68760

solution separated and evaporated, whereby the 4-phenyl- 1-Napfctalinacetic anhydride received »which without further Cleaning was suitable for use

Example 23

A mixture of 14 »4 g of 2-Dimethylaminoäthylehlorid-hydroehlorid, 26.2 g of 4-phenyl-i-naphthalene acetic acid, 20.2 g of triethylamine and 100 ml of H, ^ dimethylformamide was 19 hours heated to 85 - 90 ° C and then cooled and diluted with ether. Bas insoluble triethylamine hydrochloride was filtered off and the piltrate with excess shaken dilute hydrochloric acid. The organic layer was discarded and the acidic aqueous Layer made alkaline with sodium carbonate and using Ether extracted. The ether solution was dried, filtered and evaporated to dryness, leaving as a residue the ^ phenyl-i ^ aphtalinessigsäure ^ -dimethylaminoethyl ester The hydrochloride was obtained by dissolving the free base in Ither and treating with 1 equivalent of hydrochloric acid.

Example 24

A mixture of 13 g of _2-f 5 Diäthylaminoäthylchlorid, 26.2 g of 4-phenyl-1-naphtalineBsigeäure and 10.1 g of triethylamine in 150 ml toluene was heated for 24 hours at 100 ° C, cooled then diluted with ether. The insoluble

- 40 -

8 0 990 2/0910

Triethylamine hydrochloride was filtered off and the filtrate was stirred with excess dilute hydrochloric acid. The organic layer was discarded and the acidic aqueous layer is alkaline with potassium carbonate made and extracted with ether. The ether extract was dried, filtered and evaporated to dryness, whereby a residue of 4-phenyl-1-naphtalineasige acid-2-diethylamlnoäthylester surüokhlieh · Sas citrate by treating a solution of the free base in methanol with a solution of citric acid in methanol ten «

Substituting in the above procedure, the 4-phenyl-1-naphth Aline Bigsäure by £ 8 »0 g of 4- ^(l ml luorphenyl} .- 1-naphtalinsäure, then to obtain the 4- (m-! ^L luorphenyl) -1- naphthalene acetic acid-2-diethylamineäthyleeter and its citrate.

Example 25

line solution of 28 g of 4-pheny 1-1-naphthalene sig-boric chloride and 13.1 g of 3-diethylamino-i-propanol in 150 ml of benzene was left at room temperature for 18 hours stand «The mixture was diluted with ether, with 0.5 n-Katriuahydroxydlösung and with saturated Katrin »» Chloride solution washed, dried and under reduced

- 41 - 809902/0910

dertea Druok evaporated, whereby aalt a Eüokatand de » ^ Phenyl-i-naphthalene acetic acid ^ -diälhylaainopropyleaiiere received »The Hydroahltrid was received, Indent atan die dissolved free base in Xther and "with one equivalent of chlorine * hydrogen treated

Pattntameprücae

809902 / öItÖ

Claims (9)

Claims 1 »Procedure for making therapeutically more effective Compounds of the general formula B ² GH-OOOM daduroh characterized _f that one is a compound of the general formula werln M a Waeeeretoffatom or a salt "forming" o £ ** - lon, Y a Si * eiser carboxyl group τ # r · elfbar * group, R ² eis Waestrstoffato "or eic Me thy Ixtet""in S 'I ⁴ " la Vfc «e« retoffatoM and the other a ³ or H ⁴ a 80990 2/0910 Best of the formula is, where in this formula Z is a hydrogen atom or a fluorine, chlorine or bromine atom or an o-methyl, is m-methyl, o-methoxy or m-liethoxy radical, in an saponified in a known way " 2. The method according to claim 1, characterized in that «that one uses a compound O TL JT * where M, R and R are hydrogen atoms and E is phenyl is, 3. The method according to claim 1, characterized ge k e η η - draws that one uses a compound in which M,
rest is 2 4 3 where M, R and R are hydrogen atoms and R ^ a Ihenyl- 4 «Method according to claim 1, characterized thereby draws that one uses a connection, wherein the group saponifiable to the carboxyl group is oyan group is. - 44 - 809902/091 (K 5. The method according to claim 1, characterized that the 4-phenyl-i-naphtalineeBigsäure by heating ^ phenyl-.i-naphtylaeetonitril with an alkali hydroxide in an aqueous lower one Alkenol and subsequent acidification of the product. 6. The method naoh claim 1, characterized in that g β k e η η, that 5-phenyl-1-naphthalene acid by heating 5-phenyl-i-naphtylaeetonitrile with ei ~ an alkali hydroxide in an aqueous lower alkane! and then acidifying the product 7. Process for the preparation of compounds of the general formula f ' OH-OOOH knowing without having to “in cationic metal derivative of 4 * or 5-aryl-i-mlkyl- * naphthalene of the general formula 8 0 9 9 0 2/0910 old carbon dioxide in an anhydrous. Medium aar reacts and then acidifies the product, where in the formulas W is a reactive metal substituent, R ^{£ is} a hydrogen atom or a methyl radical, one R or R is a hydrogen atom and the other R or Br is a radical of the formula is, where in this formula Z is a hydrogen atom, a fluorine, Ohio "·" is the bromine atom or an o-methyl, m-methyl, o-methoiy or a-methoxy radical " 8. Terfahren naoh claim 7, thereby g e k e η η - It is accepted that dl · Ompp · -Mg-halogen is used as reactive metal substituents 8 0990 2/0910 9. Process for the preparation of compounds of general formula characterized in _t that a compound of the general formula CH-COOH 'Of a reactive derivative thereof with a lower * lkanol "a lower dialkylaminoalkanol or a reactive derivative thereof brings sur reaction" wherein in the Pormain R * is a lower alkyl group or a lower dialkylaminoalkyl, 2 3 E is a hydrogen atom or a methyl radical, an R 4 3 or R is a hydrogen atom and the other is R or - 47 - 809902/0910 E is a compound of the formula where in this formula Z is a hydrogen atom Fluorine, chlorine or bromine atom or an o-methyl, m- Is methyl, o-methoxy * or m-methoxy radical. 803902 / OtIO